The core aim of this project is to elucidate the nature, molecular foundations, underlying neurochemistry, and clinical correlates of neural systems-level dysfunction in schizophrenia. Toward that end, this year, the Clinical and Translational Neuroscience Branch has successfully executed comprehensive, multimodal positron emission tomography- and magnetic resonance imaging-based studies of a unique and steadily growing cohort of individuals with schizophrenia who have agreed to be studied under placebo (medication-free) conditions in comparison to matched healthy individuals. Though this work is necessarily challenging to conduct, we continue to make progress in data collection, which includes characterization of dopamine-dependent mnemonic and reward-related neural responses, striatal presynaptic dopamine synthetic capacity, and both D1 and D2/3 receptor availability, as well as prefrontal measurements of GABA and glutamate concentrations. In order to develop precision, personalized clinical care in the treatment of schizophrenia, greater neurobiological understanding is needed of the high variability across individuals in medication response. Over the past year, in efforts to address this knowledge gap, we have focused our work on identifying not only important alterations in neural systems that accompany schizophrenia in the absence of medication, but also the neurochemical predictors of neuroleptic-driven changes in brain activity and symptom burden. For example, in work focused on subcortical neural systems in schizophrenia, we have employed positron emission tomography methods to understand the functional and neurochemical consequences of antipsychotic treatment. In the dopamine receptor-rich striatum, where some individuals with schizophrenia or genetic risk factors for schizophrenia demonstrate increased dopamine synthesis capacity, resting neural activity in patients may change with neuroleptic treatment; however, whether this may be relevant to medication response and whether dopamine system characteristics underlie variance in medication-induced striatal activity changes is not established. Therefore, we studied inpatients who underwent several weeks of blinded medication withdrawal to determine PET-measured striatal regional cerebral blood flow (rCBF) and presynaptic dopamine synthesis capacity. Striatal rCBF was markedly higher during antipsychotic therapy relative to placebo. Integrating these findings in the brain with our recent work on constructing an approach to psychopathology measurement using the Positive and Negative Syndrome Scale (PANSS), we found that medication-related increases in ventral striatal rCBF were associated with more robust amelioration of excitement symptoms during active medication. Furthermore, in the ventral striatum, rCBF increases were also predicted by greater dopamine synthesis capacity during placebo treatment. These data indicate that atypical medications enact measurable physiological alterations in limbic striatal circuitry, that these alterations vary as a function of dopaminergic tone, and that they may be relevant to aspects of therapeutic response. In longitudinal studies utilizing MRS to assay GABA concentrations in the frontal cortex in patients with schizophrenia undergoing blinded medication-free periods, we found no GABA level differences when antipsychotic and placebo treatment conditions were compared. Though not establishing MRS-derived GABA levels as a robust biomarker in regard to treatment response, this negative finding serves as an important point of reference for the schizophrenia spectroscopy literature and for further neurochemical study. Finally, analyses are underway for two completed personalized-medicine drug trials examining interactions between genotype for COMT, an enzyme important for maintaining cortical dopamine, and effects of dopamine-modulating medication on cognitive function in schizophrenia. Results from these integrative, multimodal, pharmacogenetic clinical data will inform models of dopamine-linked cognitive dysfunction and remediation. This work involves the following studies: NCT00942981, NCT00001258, NCT00024622, NCT00004571, NCT00001247,NCT00001486, NCT00044083, NCT00057707